Two formidable barriers to effective drug delivery and hence to disease treatment, are solubility and stability. To be absorbed in the human body, a compound has to be soluble in both water and fats (lipids). Solubility in water is, however, often associated with poor fat solubility and vice versa.
Over 40% of drug molecules and drug compounds are insoluble in the human body. In spite of this, lipophilic drug substances having low water solubility are a growing drug class having increasing applicability in a variety in a variety of therapeutic areas and for a variety of pathologies. There are over 2500 large lipophilic molecules in various stages of development today, and over 5500 small lipophilic molecules in development (See Drug Delivery Companies Report 2001, p.2, www.pharmaventures.com). Each of the existing companies has its own restriction and limitations with regard to both large and small molecules.
Solubility and stability issues are major formulation obstacles hindering the development of therapeutic agents. Aqueous solubility is a necessary but frequently elusive property for formulations of the complex organic structures found in pharmaceuticals. Traditional formulation systems for very insoluble drugs have involved a combination of organic solvents, surfactants and extreme pH conditions. These formulations are often irritating to the patient and may cause adverse reactions. At times, these methods are inadequate for solubilizing enough of a quantity of a drug for a parenteral formulation. In such cases, doctors may administer an “overdosage”, such as for example with poorly soluble vitamins. In most cases, this overdosage does not cause any harm since the unabsorbed quantities exit the body with urine. Overdosage does, however waste a large amount of the active compound.
Although a number of solubilization technologies do exist, such as liposomes, cylcodextrins, microencapuslation, and dendrimers; each of these technologies have a number of significant disadvantages.
Phospholipids exposed to aqueous environment form a bi-layer structure called liposomes. Liposomes are microscopic spherical structures composed of phospholipids which were first discovered in the early 1960s (Bangham et al., J. Mol. Biol. 13: 238 (1965)). In aqueous media, phospholipid molecules, being amphiphilic, spontaneously organize themselves in self-closed bilayers as a result of hydrophilic and hydrophobic interactions. The resulting vesicles, referred to as liposomes, therefore encapsulate in the interior part of the aqueous medium in which they are suspended, a property that makes them potential carriers for biologically active hydrophilic molecules and drugs in vivo. Lipophilic agents may also be transported, embedded in the liposomal membrane. Liposomes resemble the bio-membranes and have been used for many years as a tool for solubilization of biological active molecules insoluble in water. They are non-toxic and biodegradable and can be used for specific target organs.
Liposome technology allows for the preparation of smaller to larger vesicles, using unilamillar (ULV) and multilamillar (MLV) vesicles. MLV are produced by mechanical agitation. Large ULV are prepared from MLV by extrusion under pressure through membranes of known pore size. The sizes are usually 200 nm or less in diameter, however, liposomes can be custom designed for almost any need by varying lipid content, surface change and method of preparation.
A number of companies such as Elan, Corp., Dublin, Ireland; Endorex Corp., Lake Forest, Ill.; Advanced Drug Deliveries Technologies, Muttenz, Switzerland; The Liposome Company, Inc., Princeton, N.J. (a subsidiary of Elan, Corp.); and Mibelle AG, Buchs, Switzerland, offer contract research and production facilities to the industry for the preparation of liposome inclusion complexes.
As drug carriers, liposomes have several potential advantages, including the ability to carry a significant amount of drug, relative ease of preparation, and low toxicity if natural lipids are used. However, common problems encountered with liposomes include: low stability, short shelf-life, poor tissue specificity, and toxicity with non-native lipids. Additionally, the uptake by phagocytic cells reduces circulation times. Furthermore, preparing liposome formulations that exhibit narrow size distribution has been formidable challenge under demanding conditions. Also, membrane clogging often results during the production of larger volumes required for pharmaceutical production of a particular drug.
Cyclodextrins are crystalline, water soluble, cyclic, non-reducing oligosaccharides built from six, seven, or eight glucopyranose units, referred to as alpha, beta and gamma cyclodextrin respectively, which have long been known as products that are capable of forming inclusion complexes. The cyclodextrin structure provides a molecule shaped like a segment of a hollow cone with an exterior hydrophilic surface and interior hydrophobic cavity.
The hydrophilic surface generates good water solubility for the cyclodextrin and the hydrophobic cavity provides a favorable environment in which enclose, envelope or entrap the drug molecule. This association isolates the drug from the aqueous solvent and may increase the drug's water solubility and stability. For a long time most cyclodextrins had been no more than scientific curiosities due to their limited availability and high price.
As a result of intensive research and advances in enzyme technology, cyclodextrins and their chemically modified derivatives are now available commercially, generating a new technology: packing on the molecular level. Companies such as Cyclolab Ltd., Budapest, Hungary; Cydex, Inc., Overland Park, Kans.; and Cyclops, Inc., Reykjavik, Iceland, have been involved in the development and manufacture of cyclodextrins.
Cyclodextrins are, however, fraught with disadvantages. An ideal cyclodextrin would exhibit both oral and systemic safety. It would have water solubility greater than the parent cyclodextrins yet retain or surpass their complexation characteristics. The disadvantages of the cyclodextrins include: limited space available for the active molecule to be entrapped inside the core, lack of pure stability of the complex, limited availability in the marketplace, and high price.
Microencapsulation is a process by which tiny parcels of a gas, liquid, or solid active ingredient are packaged within a second material for the purpose of shielding the active ingredient from the surrounding environment. These capsules, which range in size from one micron (one-thousandth of a millimeter) to approximately seven millimeters, release their contents at a later time by means appropriate to the application.
There are four typical mechanisms by which the core material is released from a microcapsule: (1) mechanical rupture of the capsule wall, (2) dissolution of the wall, (3) melting of the wall, and (4) diffusion through the wall. Less common release mechanisms include ablation (slow erosion of the shell) and biodegradation.
Microencapsulation covers several technologies, where a certain material is coated to obtain a micro-package of the active compound. The coating is performed to stabilize the material, cover for bad taste, preparing free flowing material of otherwise clogging agents etc. and many other purposes. This technology has been successfully applied in the feed-addition industry and to agriculture. The relatively high production cost needed for many of the formulations is, however, a significant disadvantage.
Dendrimers are a class of polymers distinguished by their highly branched, tree-like structures. They are synthesized in an iterative fashion from ABn monomers, with each iteration adding a layer or “generation” to the growing polymer. Dendrimers of up to ten generations have been synthesized with molecular weights in excess of 106 kDa. One important feature of dendrimeric polymers is their narrow molecular weight distributions. Indeed, depending on the synthetic strategy used, dendrimers with molecular weights in excess of 20 kDa can be made as single compounds.
Dendrimers, like liposomes, display the property of encapsulation, being able to sequester molecules within the interior spaces. Because they are single molecules, not assemblies, drug-dendrimer complexes are expected to be significantly more stable than liposomal drugs. Dendrimers are thus considered as one of the most promising vesicles for drug delivering systems. However, dendrimer technology is still in the research stage, and it is speculated that it will take years before the industry will apply this technology as a safe and efficient drug delivery system.